ASH 2021: Genetics, Your Myeloma, The Microenvironment and Your Outcomes

There were very important sessions on the biology of myeloma and how the genetics of your myeloma affect your immune system, your bone marrow microenvironment and how you respond (or don't) to myeloma therapy.

While the biology sessions at ASH are usually a little too complex for the average person (including me), these sessions provided critical clues about how we get to better personalized care.

Dr. Francesco Maura, MD from the University of Miami Sylvester Comprehensive Cancer Center reviewed all of the following studies in this video. Here's a breakdown of his important findings: 

Does Melphalan Cause Genetic DNA Damage Leading to Secondary Cancers?

This is a critical question for patients. Some patients who are treated with chemotherapies or stem cell transplant are at greater risk for secondary cancers, including leukemias or other blood disorders. Alkalyting agents like melphalan could increase the mutational burden in relapsed myeloma so the investigators studied the genetic relationship to chemo exposure. 

They studied 32 whole genomes from 31 patients (27 patients with acute myeloid leukemia and 4 with myelodysplastic syndromes). They then looked at 7 patients with either of these diseases post-auto transplant. The secondary cancer was diagnosed at a median of 4.2 years following treatment. 

Whole genome sequencing revealed the key driver role of complex structural variants (these are more than 3 breakpoint pairs involved in simultaneous copy number changes). They found that the secondary AML and myelodysplastic disorders were often driven by the patient's own stem cells that were given back following transplant after escaping the melphalan exposure. They suggest that a weakened, immunosuppressed, post-transplant environment may play a bigger role than chemotherapy causing additional genetic mutations. 

How Genetics and Dara-KRd Affect the Microenvironment and MRD Outcomes 

Eileen Boyle, MD, PhD presented work from investigators from NYU Langone, University of Miami and Memorial Sloan Kettering. This presentation won a "Best of ASH" award for academic research for the 2021 program.  

Since monoclonal antibodies like daratumumab targeting CD38 are extending life for myeloma patients, the researchers wanted to know how myeloma genetics impacted responses to daratumumab/carfilzomib/lenalidomide/dex (Dara-KRd) vs. KRd alone. They also wanted to know how the patients' immune system and bone marrow microenvironment influenced outcomes - like keeping a patient in an MRD-negative state. 

They tested 60 myeloma patient tumors in newly diagnosed myeloma patients and used whole genome sequencing to look at mutational driver genetics compared to normal bone marrow without myeloma. They then associated that with patients who did or didn't achieve MRD negativity. They also did single cell analysis of the immune microenvironment for a subset of patients prior to therapy. 

They sampled patients after induction therapy (but before transplant) and then a year following. After median follow up of 29 months, 54% of patients achieved MRD negativity, 51% had sustained MRD negativity for more than one year but 15% of these patients progressed or went from MRD negative to MRD positive. 

Patients who DID NOT achieve MRD negativity included those with the following mutations: 

• Del13 patients
• Del 22q patients (XBP1 regulates CD38 expression and could reduce the CD38 target)
• Patients who lost both copies of 16q
• Del 20q patients
• Gain of 8q patients
• (You will notice that some of these genetic mutations are not currently tested on today's myeloma FISH tests)

 Patients who DID achieve MRD negativity but then LOST MRD negativity included: 

• Del1 1p patients
• Patients with a high tumor burden

Patients who DID achieve and sustain MRD negativity included:

• Patients with trisomy of 21

Overall, their findings highlight potential new genomic drivers associated with resistance to D-KRd.

• The del22 patients had fewer memory B-cells, fewer naïve B-cells and fewer dendritic cells compared to normal cells.
• Patients with the del20 also had fewer dendritic cells. Having low dendritic cells was linked to not being able to achieve or stay MRD negative. 
• They looked at treatment responses associated with the microenvironment and noticed that there was a profound B-cell depletion. They wanted to know if that was connected to remaining MRD negative. There was a striking loss of B-cells for patients who stayed MRD negative. 
• They also found that inflammatory genes were enhanced for patients with detectable disease.
• Patients who stayed MRD negative also had more CD14 positive monocytes (which are considered "normal" monocytes and have no inflammatory attributes.)

Dr. Boyle concluded by saying that there was a complex relationship between tumor genetics, the immune system microenvironment and response to treatment, at least for the Dara-KRd combination.  If the proper tests were run prior to therapy, this type of information could pre-determine who may or may not respond to certain therapies based on their genetics going into therapy. The new genetics identified are also of importance and interest.

What is the Role of Lenalidomide Maintenance on the Immune System and MRD Negativity? 

David Coffey, MD of the Fred Hutchinson Research Center along with researchers from the University of Miami Sylvester Comprehensive Cancer Center and Princess Margaret Cancer Centre shared research on the immune system. The researchers wanted to know the impact of lenalidomide maintenance on the immune system by comparing patients who achieved MRD negativity compared to those who didn't. 

They used single cell RNA sequencing with additional testing on blood and bone marrow samples before and about one year after starting maintenance therapy. Before maintenance therapy 46% of patients had received induction and auto stem cell transplant, 54% had induction therapy but no transplant. 

Patient Immune System Characteristics Who Achieved Better Outcomes

Before starting therapy, patients who had sustained MRD negativity had more naïve CD8+ T cells in their pre-treatment sample. Following treatment (regardless of transplant vs. no transplant), patients who had sustained MRD negativity also had higher levels of circulating naïve CD4+ T cells during therapy. Patients with sustained MRD negativity also had increased vascular endothelial growth factor (VEGF) levels. Patients with sustained responses see their immune system normalize following treatment compared to patients with worse outcomes. 

Patient Immune System Characteristics Who Achieved Worse Outcomes

The study found that patients who had early progression had more circulating regulatory T cells increased during maintenance therapy. They has had a greater number of NK cells in the bone marrow. Patients with progressive disease saw their immune system depressed prior to treatment and during follow-up.